Ground- and Excited-State Interactions of a Psoralen Derivative with Human Telomeric G-Quadruplex DNA.

Abstract

G-quadruplex DNA has been a recent target for anticancer agents, and its binding interactions with small molecules, often used as anticancer drugs, have become an important area of research. Considering that psoralens have long been studied in the context of duplex DNA but that very little is known about their potential as G-quadruplex binders and their excited-state interaction with the latter has not been explored, we have studied herein the binding of a planar water-soluble psoralen derivative, 4'-aminomethyl-4,5',8-trimethylpsoralen (AMT), with the 22-mer human telomeric G-quadruplex-forming sequence, AGGG(TTAGGG)3, labeled here as (hTel22), and investigated the consequences of photoexcitation of AMT by calorimetric and spectroscopic techniques. The results show an enthalpy-driven 1:1 binding of AMT with hTel22 via end-stacking mode. Fluorescence quenching experiments on 6-fluorescein amidite-labeled oligomers indicate that the binding site is nearer to the 3' end of hTel22 in the diagonal loop region. Femtosecond time-resolved transient absorption measurements indicate electron transfer from the guanine moiety of hTel22 to photoexcited AMT, leading to the formation of a radical pair species (AMT•-G•+), which survives for 30 ps and is favored by a parallel/quasi-parallel orientation between the two. The findings reveal psoralens as a prospective class of compounds for the development of anticancer therapeutics by targeting the G-quadruplex DNA.